Aza-amino acid derivatives (factor Xa inhibitors 15)

ABSTRACT

The invention relates to semicarbazides of the general formula I 
                 
 
where R 1 , R 2 , R 3 , R 4  and I have the meaning indicated in claim  1.  
 
     The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, mycocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

The invention relates to semicarbazides of the general formula I,

where:

-   -   R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or        —C(═NH)—NH₂, which can also be monosubstituted by —OH, —OCOOA,        —OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA,        —COSA, —COOAr, —COOAr′        or by    -   R² is H, COOA,    -   R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms,        in which one or two CH₂ groups can be replaced by O or S atoms,        or is Ar, Ar′, X or Hal,    -   R⁴ is phenyl monosubstituted by S(O)_(k)A, S(O)_(k)NHA, CF₃,        COOA, CH₂NHA, CN or OA,    -   R⁵ is —CHal₃, —O(C═O)A or    -   Ar is phenyl or naphthyl, which is unsubstituted or mono-, di-        or trisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN,        Hal, NHCOA, COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂,        S(O)_(n)NHA, S(O)_(n)NA₂,    -   Ar′ is —(CH₂)_(n)—Ar,    -   Het is a mono- or binuclear, saturated, unsaturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, bonded via N or        C, which can be unsubstituted or substituted by A,    -   A is H, unbranched, branched or cyclic alkyl having 1-20 C        atoms,    -   X is —(CH₂)_(n)—Y,    -   Y is COOA,    -   Hal is F, Cl, Br or I,    -   n is 1, 2, 3, 4, 5 or 6,    -   m is 0 or 1,    -   k is 0, 1 or 2,    -   l is 0, 1, 2, 3 or 4,        and their pharmaceutically tolerable salts and solvates.

The invention also relates to the optically active forms, the racemates,the diastereomers and also the hydrates and solvates, e.g. alcoholates,of these compounds.

For the control of hemorrhages caused by injuries, the human body has amechanism by means of which, with the aid of blood clots, a rapid woundclosure is achieved. Blood clots are formed by a series of zymogenactivations. In the course of this enzymatic cascade, the activated formof a factor in each case catalyzes the activation of the next. Sincethis process is of catalytic nature, very small amounts of thetriggering factor suffice to set the cascade in motion. As a result ofthe large number of steps, a large amplification is achieved, whichguarantees a rapid response to the injury. The plasmatic clotting aftera tissue lesion can take place exogenously due to the release of tissuethrombokinase. The corresponding reaction sequence is designated as anextravascular system (extrinsic system) and proceeds within seconds. Theclotting can also be triggered endogenously by thrombocytolysis. Thisreaction sequence, which is designated as an intravascular system,proceeds within minutes. Both systems result in a final common sequenceof steps which lead to the formation of a blood clot. The intravascularand the extravascular system have a mutual influence in vivo. Both arenecessary for the complete course of blood clotting.

Rapid blood clotting is so important for the closure of injuries, incertain disorders it is actually necessary to inhibit blood clotting inorder, for example, to avoid the formation of thrombi in vessels. Inthis case, an intervention should be made as specifically andselectively as possible into the blood clotting cascade in order to beable to control the inhibition as precisely as possible and to be ableto avoid undesired side effects.

Factor X_(a) is a serine protease of the blood clotting cascade, whichis formed by activation of factor X. In the intravascular pathway, thisactivation is carried out by factor IX_(a), this reaction beingstimulated by the antihemophilic factor (VIII_(a)). By means of factorX_(a), prothrombin is then converted into thrombin. The proteolyticenzyme thrombin cleaves fibrinogen into fibrin monomers, which arrangespontaneously to give ordered fibrous structures, which are designatedas fibrin. The clot that results due to the spontaneous aggregation offibrin monomers is stabilized by covalent crosslinkages between the sidechains of various molecules in the fibrin fibers. To this end, peptidebonds are formed between specific glutamine and lysine side chains in atransamidation reaction. This crosslinkage is catalyzed by an enzymewhich is designated as factor XIII_(a).

In the extravascular system, the activation of factor X is carried outby the tissue factor and factor VII.

Inhibition of factor X_(a) allows specific intervention into bloodclotting, since no other processes are influenced here. It is moreadvantageous than, for example, inhibition of thrombin, since thrombinon the one hand catalyzes the conversion of fibrinogen to fibrin, andalso the conversions of factor VIII into factor VIII_(a), factor V intoV_(a) and factor XI into XI_(a), and on the other hand, for example,also activates platelets. A variety of research activities havetherefore been undertaken to develop inhibitors of factor X_(a), whichhave led to the development of various classes of substance.

WO 99/11657 describes 1-amino-7-isoquinoline derivatives which act asinhibitors of serine proteases. WO 99/11658 describe m-benzamidinederivatives which act as serine protease inhibitors. Furthermore, WO99/10316 describes 3-amidinoaniline derivatives which act as inhibitorsof activated blood clotting factor X_(a).

It is an object of the invention to discover novel compounds havingvaluable properties, in particular those which can be used for theproduction of medicaments.

It has been found that the compounds of the formula I and their saltshave very valuable pharmacological properties, together with goodtolerability. In particular, they exhibit factor X_(a)-inhibitingproperties and can therefore be employed for the control and preventionof thromboembolic disorders, such as thrombosis, myocardial infarct,arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosisafter angioplasty and intermittent claudication.

The compounds of the formula I according to the invention canfurthermore be inhibitors of the blood clotting factors VII_(a), IX_(a)and thrombin of the blood clotting cascade.

The inhibition of thrombin can be measured, for example, by the methodof G. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

The inhibition of factor X_(a) by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined according to customary in vitro or in vivomethods. A suitable procedure is described, for example, by J. Hauptmannet al. in Thrombosis and Haemostasis, 1990, 63, 220-223.

The measurement of the inhibition of factor X_(a) can be carried out,for example, according to the method of T. Hara et al. in Thromb.Haemostas., 1994, 71, 314-319.

The inhibition of factor VII_(a) by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined according to customary in vitro or in vivomethods. A customary procedure for the measurement of the inhibition offactor VII_(a) is described, for example, by H. F. Ronning et al. inThrombosis Research 1996, 84, 73-81.

The inhibition of factor IX_(a) by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined according to customary in vitro or in vivomethods. A suitable procedure is described, for example, by J. Chang etal. in Journal of Biological Chemistry 1998, 273, 12089-12094.

The compounds of the formula I can be employed as pharmaceutical activecompounds in human and veterinary medicine, in particular for thecontrol and prevention of thromboembolic disorders such as thrombosis,myocardial infarct, arteriosclerosis, inflammation, apoplexy, anginapectoris, restenosis after angioplasty and/or intermittent claudication.Furthermore, they are applicable for the treatment of tumors, tumordiseases and/or tumor metastases. A relation between the tissue factorTK/factor VIIa and the development of various types of cancer has beenshown by T. Taniguchi et al. in Biomed. Health Res. (2000), 41(“Molecular Pathogenesis of Pancreatic Cancer”), 57-59.

The semicarbazides according to the invention particularly preferablyhave a structure of the formula II

where R¹, R³, A and k have the meaning indicated in claim 1 and W isS(O)_(k)A, S(O)_(k)NHA, CF₃, COOA, CH₂NHA, CN or OA.

Compounds which are particularly to be emphasized are mentioned below:

-   -   4′-[3-(3-amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide        (1),    -   4′-[3-(3-(N²-hydroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide        (2),    -   4′-[3-(3-amidinophenyl)-2-methylcarbazoylamino]biphenyl-2-sulfonamide        (3),    -   1-(3-amidinophenyl)-2-methyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (4),    -   4′-[3-(3-amidinophenyl)-2-ethylcarbazoylamino]biphenyl-2-sulfonamide        (5),    -   1-(3-amidinophenyl)-2-ethyl4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide        (6),    -   4′-[3-(3-amidinophenyl)-2-isopropylcarbazoylamino]biphenyl-2-sulfonamide        (7),    -   1-(3-amidinophenyl)-2-isopropyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (8),    -   4′-[3-(3-amidinophenyl)-2-butylcarbazoylamino]biphenyl-2-sulfonamide        (9),    -   1-(3-amidinophenyl)-2-butyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (10),    -   4′-[3-(3-amidinophenyl)-2-isobutylcarbazoylamino]biphenyl-2-sulfonamide        (11),    -   1-(3-amidinophenyl)-2-isobutyl4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (12),    -   4′-[3-(3-amidinophenyl)-2-pentylcarbazoylamino]biphenyl-2-sulfonamide        (13),    -   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-pentylsemicarbazide        (14),    -   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide        (15),    -   4′-[3-(3-amidinophenyl)-2-(2-butyl)carbazoylamino]biphenyl-2-sulfonamide        (16),    -   1-3-amidinophenyl)-2-(2-butyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (17),    -   4′-[3-(3-amidinophenyl)-2-(cyclohexylmethyl)carbazoylamino]biphenyl-2-sulfonamide        (18),    -   1-(3-amidinophenyl)-2-(cyclohexylmethyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (19),    -   4′-[3-(3-amidinophenyl)-2-benzylcarbazoylamino]biphenyl-2-sulfonamide        (20),    -   1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (21),    -   1-(3-N-2-hydroxyamidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (22),    -   4′-[3-(3-amidinophenyl)-2-phenylcarbazoylamino]biphenyl-2-sulfonamide        (23),    -   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylsemicarbazide        (24),    -   methyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (25),    -   2,2,2-trichloroethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (26),    -   S-ethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]thiocarbamate        (27),    -   4-methoxybenzyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (28),    -   ethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (29),    -   propyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (30),    -   butyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (31),    -   isopropyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (32),    -   isobutyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (33),    -   allyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (34),    -   phenyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate        (35),    -   2-fluorophenyl        N-[3-[2-benzyl4-(2′-methylsulfonylbiphenyl4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (36),    -   2-benzyl-1-[3-(N¹-(methylcarboxy)amidino)phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (37),    -   2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-1-[3-(N¹-(phenylcarboxy)amidino)phenyl]semicarbazide        (38),    -   2-benzyl-1-[3-(N¹-(isobutylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (39),    -   2-benzyl-1-[3-[N¹-(2-methylcarboxy-2-propoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (40),    -   2-benzyl-1-[3-[N¹-(1-(methylcarboxy)ethoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (41),    -   1-methyl-4-piperidinyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (42),    -   2-(4-pyridyl)ethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (43),    -   5-methyl-2-oxo-1,3-dioxol-4-ylmethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (44),    -   2-(3-pyridyl)ethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (45),    -   2-(N,N-diethylamino)ethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (46),    -   2-(N-morpholinyl)ethyl        N-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate        (47),    -   1-(3-amidinophenyl)-2-(2-fluorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (48),    -   1-(3-amidinophenyl)-2-(2-methylbenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide        (49),    -   1-(3-amidinophenyl)-2-(2-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide        (50),    -   1-(3-amidinophenyl)-2-(3-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (51),    -   4-[1-(3-amidinophenylamino)-3-(2′-methylsulfonylbiphenyl-4-yl)ureidomethyl]-benzoic        acid (52),    -   1-(3-amidinophenyl)-2-(3-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (53),    -   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethyl        -benzyl)semicarbazide (54),    -   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethyl        -benzyl)semicarbazide (55),    -   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethoxy        -benzyl)semicarbazide (56),    -   1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide        (57),    -   1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide        (58),    -   1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide        (59),    -   1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (60),    -   1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide        (61),    -   1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide        (62),    -   1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide        (63),    -   1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide        (64),    -   1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide        (65),    -   ethyl        2-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-acetate        (66),    -   ethyl        3-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-propionate        (67),    -   4′-[3-(3-amidinophenyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]carbazoylamino]-biphenyl-2-sulfonamide        (68),    -   4′-[3-(3-amidinophenyl)-2-(2-methoxyethyl)carbazoylamino]biphenyl-2-sulfonamide        (69),    -   4′-[3-(3-amidinophenyl)-2-(methoxymethyl)carbazoylamino]biphenyl-2-sulfonamide        (70),    -   4′-[3-(3-amidinophenyl)-2-(4-methoxybutyl)carbazoylamino]biphenyl-2-sulfonamide        (71),    -   1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (72),    -   1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoro        -methylbenzyl)semicarbazie (73),    -   1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoro        -methylbenzyl)semicarbazie (74),    -   1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoro        -methylbenzyl)semicarbazie (75),    -   1-(3-aminomethylphenyl)-2-benzyl-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)semicarbazide        (76),    -   1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide        (77),    -   1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide        (78),    -   1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide        (79).    -   1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (80),    -   1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (81),    -   1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide        (82),    -   1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide        (83),    -   1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (84),    -   1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide        (85),    -   1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide        (86),    -   1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide        (87),    -   1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide        (88),    -   2-Benzyl-1-[3-(N¹-methoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (89),    -   2-Benzyl-1-[3-(N1-ethoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (90),    -   2-Benzyl-1-[3-(N1-vinyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (91),    -   2-Benzyl-1-[3-(N1-benzyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (92),    -   2-Benzyl-1-[3-(N1-isopropoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (93),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (94),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (95),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide        (96),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide        (97),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide        (98),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide        (99),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide        (100),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3,5-difluorobiphenyl-4-yl)-semicarbazide        (101),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide        (102),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide        (103),    -   1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide        (104).

Particular embodiments of the compounds of the formula I are mentionedbelow, a generalized form of the group of compounds being indicated inthe tables.

The coefficients indicated in the formulae correspond to the meaningsindicated above. In the case of the examples synthesized for theindividual groups of compounds, the FAB values measured are indicated ineach case if available.

In table 1, examples are mentioned for compounds in which the variousalkyl radicals R³ are introduced into the molecular structure. In thediphenyl moiety, the sulfonamide derivatives and the methylsulfonylderivatives were prepared by variation of the group Y, which is an aminoor a methyl group.

TABLE 1

Number R¹ R³ Z FAB 1

—NH₂ 467 2

—NH₂ 483 3

—NH₂ 4

—CH₃ 5

—NH₂ 6

—CH₃ 7

—NH₂ 8

—CH₃ 9

—NH₂ 10

—CH₃ 11

—NH₂ 12

—CH₃ 13

—NH₂ 14

—CH₃ 15

—CH₃ 446

Examples in which the radical R³ is constructed as a cycloalkyl radicalor as an aromatic radical are shown in table 2. Here too, sulfonamidederivatives and methylsulfonyl derivatives were prepared by variation ofthe group Z.

TABLE 2

Number R¹ R³ Z FAB 16

—NH₂ 17

—NH₂ 18

—NH₂ 19

—CH₃ 20

—NH₂ 515 21

—CH₃ 514 22

—CH₃ 530 23

—NH₂ 24

—CH₃

The compounds of the formula I can also be constructed as prodrugs.After absorption into the blood circulation, the compounds are cleavedenzymatically and the active compound is released. In table 3, variouspossibilities for prodrugs are presented with the aid of an activecompound.

The absorption rate and the rate of release of the active compound, forexample, can be influenced by the variation of the radical R¹. Theexamples of the group R¹ indicated in table 3 can be transferred withoutproblems to other active compounds of the formula I, such as, forexample, are shown in tables 1 and 2.

TABLE 3

Number R¹ FAB 25

572 26

690 27

28

678 29

586 30

31

614 32

600 33

614 34

598 35

634 36

652

Further examples of variation of the radical R¹ for preparation ofprodrugs are indicated in table 4. The preparation of the prodrugs shownin tables 3 and 4 is carried out analogously to the procedures which aredescribed in S. N. Rahamthullah et al J. Med. Chem. 1999, 42, 3994-4000.

TABLE 4

Number R¹ FAB 37

572 38

634 39

614 40

672 41

42

692 43

44

45

46

47

89

90

91

92

99

By substitution of the alkyl or aryl groups introduced as the radical R³by, for example, halogen atoms, alkyl groups or carboxyl groups, thepolarity of the molecule can be influenced. The compound becomes morelipophilic as a result of the introduction of fluorine atoms and istherefore more easily absorbed. Examples of compounds of this type areshown in table 5. In this case, the group R³ was varied for a specificactive compound. A variation of this type can also be carried outwithout problems for other radicals R¹ and R⁴.

TABLE 5

Number R³ B C FAB 48

H H 49

H H 50

H H 51

H H 52

H H 53

H H 54

H H 582 55

H H 582 56

H H 57

H F 532 58

H F 600 59

H F 600 60

H H 582 61

H F 600 62

F F 550 63

F F 618 64

F F 618 65

F F 618

Further examples of the radicals R³ which contain heteroatoms are shownin table 6. The variation of the radical R³ was in this case performedby way of example on a sulfonamide derivative.

TABLE 6

Number R³ FAB 66

67

68

69

70

71

Examples in which the lipophilicity of a part of the compounds wasvaried are shown in table 7. Here, in a part of the compounds, theradical R³ includes a trifluoromethyl group. Furthermore, in some of thecompounds, one or two fluorine atoms were introduced into the biphenylmoiety of the molecule. The variation can be transferred to the othercompounds of the formula I without problems.

TABLE 7

Number R³ B C RAB 72

H H 73

H H 74

H H 75

H H 76

F H 77

F H 78

F H 79

F H 587 80

H H 569 81

H H 569 82

F H 519 83

F H 587 84

H H 501 85

H F 587 86

F F 537 87

F F 605 88

F F 605

Further compounds are shown in table 8.

TABLE 8

Number R³ B C FAB 94

H H 598 95

H H 598 96

F H 548 97

F H 616 98

F H 616 99

H H 598 100

F H 616 101

F F 566 102

F F 634 103

F F 634 104

F F 634

The structural elements of the compounds according to the inventionshown above with the aid of selected compounds can be combinedarbitrarily. The compounds can thereby be tailored to the intendedtherapeutic use.

The compounds of the formula I can be prepared by processes known perse. Some exemplary synthesis routes are presented below.

The synthesis of the molecular structure is explained with the aid ofscheme 1.

The synthesis starts from the bromobenzene derivative 501. The radicalR¹ is preferably a group which can be converted into an amidino group ata later point in time in the synthesis. Appropriate structural elementsare presented further below. The bromine forms the leaving group for thereaction with the protected hydrazine derivative 502 (Wang Z. et al.Tetrahedron Lett. 1999, 40, 3543-3546). The bromine atom can thereforealso be replaced by other suitable leaving groups, for example otherhalides or sulfonates. The hydrazine derivative 502 has a protectivegroup P. The protective groups used can be customary protective groupsfor amino groups. A particularly suitable protective group is the BOCprotective group. The protected phenylhydrazine derivative 503 isobtained by reaction of the compounds 501 and 502. The free NH₂ group isprotected in the next reaction step by the protective group P′. Theintermediate III is obtained. If possible, the protective groups P andP′ are chosen differently in order to make possible selectivedeprotection of the two nitrogen atoms. The protective group P′ usedcan, as explained above, be the protective groups for amino groups knownto the person skilled in the art. Next, the introduction of the radicalR³ is carried out, in which, for example, the compound III is reactedwith an alkyl halide to give the compound IV. Compound IV is thenselectively deprotected on the terminal nitrogen with obtainment of thecompound V. By reaction with optionally F substituted iodophenylisocyanate, the compound VI is obtained. The iodine atom in compound VIcan be substituted, whereby the radical R⁴ can be introduced into themolecule. Compound VII is obtained. The radical R⁴ is present here insuitably protected form. Examples are illustrated further below.Together with the radicals R¹, P and R⁴, the compound VII in generaladditionally contains protected structural elements. The removal of theprotective group P is carried out according to customary processes, forexample using acid.

Scheme 2 shows suitable radicals R¹, which remain unchanged in thereaction steps presented above and can then be released starting fromcompound VII. For reasons of clarity, only the phenyl group having theradical R¹ is shown in scheme 2.

The first possibility consists in the introduction of a nitrile group.This can be converted into the hydroxyamidino group (505) usinghydroxylammonium chloride and triethylamine. These compounds can alreadybe used as prodrugs. The amidino group (506) is released by reductionwith Raney nickel under a hydrogen atmosphere. The aminomethylderivative (512) is likewise formed from the nitrile (504) by reduction.

A further possibility is shown under b). This group (507) can likewisebe converted into the amidino group (506) using Raney nickel andhydrogen.

In scheme 3, possibilities are presented which allow the introduction ofa sulfonamide group (a) and of a methylsulfonyl group (b). Here too, forreasons of clarity only the essential molecular entity (R³) is shown.

For the protection of sulfonamides, the amino group is suitablyprotected. Under (a), the nitrogen, for example, is protected with atert-butyl group. The removal of the group is carried out using acid,e.g. trifluoroacetic acid.

To introduce the methylsulfonyl group, the corresponding methylthiocompound (510) is used as a starting compound. Starting from thecorresponding compound VII, the methylthio group is oxidized to themethylsulfonyl compound 511, for example, using sodium perboratetrihydrate in acetic acid.

The reaction schemes indicated above can be varied by the person skilledin the art without problems. For example, other leaving or protectivegroups can be employed. If racemic mixtures are obtained in thereactions, diastereomers can be formed from these in the customarymanner by reaction with an optically active resolving agent, and arethen separated according to customary processes. A chromatographicresolution of enantiomers with the aid of an optically active resolvingagent (e.g. dinitrobenzylphenylglycine, cellulose triacetate or otherderivatives of carbohydrates or chirally derivatized methacrylatepolymers attached to kieselguhr) is also advantageous.

The invention further relates to the use of the compounds of the formulaI and/or their physiologically acceptable salts for the production ofpharmaceutical preparations, in particular by a non chemical route. Inthis connection, they can be brought into a suitable dose form, togetherwith at least one solid, liquid and/or semiliquid vehicle or excipientand if appropriate in combination with one or more further activecompounds.

The invention further relates to pharmaceutical preparations comprisingat least one compound of the formula I and/or one of its physiologicallyacceptable salts.

These preparations can be used as medicaments in human or veterinarymedicine. Possible vehicles are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates suchas lactose or starch, magnesium stearate, talc and petroleum jelly. Inparticular, tablets, pills, coated tablets, capsules, powders, granules,syrups, juices or drops are suitable for oral administration,suppositories are suitable for rectal administration, solutions,preferably oily or aqueous solutions, furthermore suspensions, emulsionsor implants, are suitable for parenteral administration, and ointments,creams or powders are suitable for topical application. The novelcompounds can also be lyophilized and the lyophilizates obtained used,for example, for the production of injection preparations. Thepreparations indicated can be sterilized and/or can contain excipients,such as lubricants, preservatives, stabiizers and/or wetting agents,emulsifiers, salts for influencing the osmotic pressure, buffersubstances, colorants, flavorings and/or one or more further activecompounds, e.g. one or more vitamins.

The compounds of the formula I and their physiologically acceptablesalts can be used in the control and prevention of thromboembolicdisorders such as thrombosis, myocardial infarct, arteriosclerosis,inflammation, apoplexy, angina pectoris, restenosis after angioplastyand intermittent claudication.

As a rule, the substances according to the invention are preferablyadministered here in doses of between 1 and 500 mg, in particularbetween 5 and 100 mg, per dose unit. The daily dose is preferablybetween approximately 0.02 and 10 mg/kg of body weight. The specificdose for each patient depends, however, on various factors, for exampleon the efficacy of the specific compound employed, on the age, bodyweight, general state of health, sex, on the diet, on the time and routeof administration, and on the excretion rate, pharmaceutical combinationand severity of the particular disorder to which the therapy relates.Oral administration is preferred.

The invention is illustrated in greater detail with the aid of examples.

EXAMPLE A

Synthesis4′-[3-(3-amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide 1

The synthesis is shown in scheme 4.

tert-Butyl 2-(3-cyanophenyl)carbazate 401

50.0 g (0.275 mol) of 3-bromobenzonitrile in 400 ml of THF are treatedunder a nitrogen atmosphere with 36.345 g (0.275 mol) of tert-butylcarbazate, 89.6 g (0.275 mol) of cesium carbonate, 1.581 g (0.003 mol)of bis(dibenzylideneacetone)palladium and 4.602 g (0.008 mol) of1,1′-bis(diphenylphosphino)ferrocene and the mixture is then stirred at110° C. for 18 h. After cooling and customary work-up, 15.8 g (24.7%) of401 are obtained as an oil; MS(FAB)=234. [The reaction is carried outanalogously to a procedure of Wang et al. Tetrahedron Lett. 1999, 40,3543].

tert-Butyl 2-(3-cyanophenyl)-3-(2,2,2-trifluoroacetyl)carbazate 402

10.7 g (46 mmol) of 401 are treated with 9.54 ml (68.8 mmol) oftriethylamine in 200 ml of THF. 7.02 ml (50.46 mmol) of trifluoroaceticanhydride are slowly added dropwise with cooling to 5° C. After stirringfor 6 h, the mixture is worked up in the customary manner and 14.3 g(94.7%) of 402 are thus obtained as an oil, which is employed directlyin stage 3.

tert-Butyl 2-(3-cyanophenyl)-3-propyl-3-(2,2,2-trifluoracetyl)carbazate403

5.0 g (15.19 mmol) of the crude product 402 are treated with 7.42 g(22.77 mmol) of cesium carbonate in 100 ml of DMF under a nitrogenatmosphere. After 30 min, 3.87 ml (22.77 mmol) of 1-iodopropane areslowly added dropwise and the mixture is then stirred at RT for 18 h.After customary work-up, 5.64 g (100%) of 403 are thus obtained as anoil, which is employed directly in stage 4.

tert-Butyl 2-(3-cyanophenyl)-3-propylcarbazate 404

5.64 g (15.187 mmol) of crude product 403 are dissolved in 100 ml ofmethanol and treated at RT with 10 ml of completely deionized water and1.08 g (45.24 mmol) of lithium hydroxide. The reaction mixture is thenstirred for 5 h. After customary work-up, 2.67 g (63.8%) of 404 are thusobtained as an oil; MS(FAB)=276.

tert-Butyl2-(3-cyanophenyl)-3-(4-iodophenylaminocarbonyl)-3-propylcarbazate 405

2.0 g (7.273 mmol) of 404 are stirred at RT for 1.5 h in 5.0 ml ofpyridine with 1.78 g (7.265 mmol) of 4-iodophenyl isocyanate. Aftercustomary work-up, 3.2 g (84.7%) of 405 are thus obtained as crystalshaving a melting point of 184-185° C.; MS(FAB)=521.

4′-[3-tert-Butoxycarbonyl-3-(3-cyanophenyl)-2-propylcarbazoylamino]-N-tert-butylbiphenyl-2-sulfonamide406

1.5 g (2.883 mmol) of 405 and 1.112 g (4.324 mmol) of2-(t-butylamino-sulfonyl)phenylboronic acid are dissolved in 100 ml ofethylene glycol dimethyl ether, treated with 63 mg (0.086 mmol) ofPdCl₂(dppf) and 20.0 ml of 2N sodium carbonate solution and then stirredat 110° C. under a nitrogen atomsphere for 3 h. After customary work-up,1.32 g (75.6%) of 406 are thus obtained as crystals having a meltingpoint of 173-174° C.; MS(FAB)=606.

4′-[3-tert-Butoxycarbonyl-3-[3-(N¹-hydroxyamidino)phenyl]-2-propylcarbazoylamino]-N-tert-butylbiphenyl-2-sulfonamide407

A suspension of 1.0 g (1.651 mmol) of 406 in 25.0 ml of ethanol aretreated with 0.459 g (6.604 mmol) of hydroxylammonium chloride and 0.916ml (6.604 mmol) of triethylamine and the mixture is stirred under refluxfor 5 h. After customary work-up, 1.05 g (99.6%) of 407 are thusobtained as crystals having a melting point of 218-219° C.; MS(FAB)=639.

4′-[3-(3-Amidinophenyl)-3-tert-butoxycarbonyl-2-propylcarbazoylamino]-N-tert-butylbiphenyl-2-sulfonamide408

0.7 g (1.096 mmol) of 407 is dissolved in 10.0 ml of methanol, treatedwith 0.25 ml of acetic acid and 0.3 g of water-moist Raney nickel andthe mixture is stirred under an H₂ atmosphere for 18 h. After customarywork-up, 0.62 g (90.8%) of 408 is thus obtained as crystals having amelting point of >300° C.; MS(FAB)=623.

4′-[3-(3-(N-2-Hydroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(2)

0.2 g (0.313 mmol) of 407 is dissolved in 5.0 ml of trifluoroacetic acidand the solution is stirred at 5° C. for 18 h. After customary work-up,0.15 g (99.3%) of 2 is thus obtained as crystals having a melting pointof 163-164° C.; MS(FAB)=483.

4′-[3-(3-Amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(1)

0.5 g (0.803 mmol) of 408 is dissolved in 5.0 ml of trifluoroacetic acidand stirred at 5C for 18 h. After customary work-up, 0.15 g (99.3%) of 1is thus obtained as crystals having a melting point of 215-216° C.;MS(FAB)=467.

EXAMPLE B

Synthesis of1-(3-amidinophenly)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide15

The synthesis is shown in scheme 5:

tert-Butyl2-(3-cyanophenyl)-3-(2′-methylthiobiphenyl-4-ylaminocarbonyl)-3-propylcarbazate409

1.5 g (2.883 mmol) of 405 and 0.968 g (5.766 mmol) of2-(methylthio)-phenylboronic acid are dissolved in 100 ml of ethyleneglycol dimethyl ether, treated with 63 mg (0.086 mmol) of PdCl₂(dppf)and 20.0 ml of 2N sodium carbonate solution and then stirred at 110° C.under a nitrogen atmosphere for 3 h. After customary work-up, 1.28 g(75.9%) of 409 are thus obtained as crystals having a melting point of184-185° C.; MS(FAB)=517.

tert-Butyl2-(3-cyanophenyl)-3-(2′-methylsulfonylbiphenyl-4-ylaminocarbonyl)-3-propylcarbazate410

0.8 g (1.548 mmol) of 409 is suspended in 15 ml of acetic acid with1.433 g (9.312 mmol) of sodium perborate trihydrate and the mixture isstirred at 60° C. for 18 h. After customary work-up, 0.65 g (76.5%) of410 is thus obtained as crystals having a melting point of 194-195° C.;MS(FAB)=549.

tert-Butyl 2-[3-(N¹-hydroxyamidino)phenyl]-3-(2′-methylsulfonylbiphenyl-4-ylaminocarbonyl)-3-propylcarbazate411

A solution of 0.6 g (1.094 mmol) of 410 is dissolved in 25 ml ofethanol, treated with 0.304 g (4.376 mmol) of hydroxylammonium chlorideand 0.608 ml of (4.376 mmol) of triethylamine and then stirred underreflux for 18 h. After customary work-up, 0.11 g (17.3%) of 411 is thusobtained as crystals having a melting point of 187-188° C.; MS(FAB)=582.

1-(3-N²-Hydroxyamidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide413

50.0 mg (0.086 mmol) of 411 are dissolved in 1.0 ml of 4N HCl indioxane. and the solution is stirred at RT for 18 h. After customarywork-up, 0.11 g (17.3%) of 413 is thus obtained as crystals having amelting point of 195-196° C.; MS(FAB)=482.

tert-Butyl2-(3-amidinophenyl)-3-(2′-methylsulfonylbiphenyl4-ylaminocarbonyl)-3-propylcarbazate412

0.2 g (0.344 mmol) of 411 is dissolved in 5.0 ml of methanol, treatedwith 0.1 ml of acetic acid and 0.1 g of water-moist Raney nickel and themixture is stirred under an H₂ atmosphere for 18 h. After customarywork-up, 0.19 g (100%) of 412 is thus obtained as crystals having amelting point of >300° C.; MS(FAB)=566.

1-(3-Amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide15

0.2 g (0.354 mmol) of 412 is dissolved in 10 ml of 4N HCl in dioxane andthe mixture is stirred at RT for 18 h. After customary work-up, 0.13 g(76.9%) of 15 is thus obtained as crystals having a melting pointof >300° C.; MS(FAB)=466.

1. A semicarbazide of formula I,

wherein: R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R² is H, or COOA, R³ is unbranched, branched or cyclic alkyl having 1-20C atoms, in which one or two CH₂ groups are optionally eachindependently of one another replaced by an O or S atom, or is Ar, Ar′,X or Hal, R⁴ is phenyl monosubstituted by S(O)_(k)A, S(O)_(k)NHA, CF₃,COOA, CH₂NHA, CN or OA, R⁵ is —CHal₃, —O(C═O)A or

Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, A is H, unbranched, branched or cyclic alkyl having1-20 C atoms, X is —(CH₂)_(n)—Y, Y is COOA, or

Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 0 or 1, k is 0, 1or 2, and i is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt orsolvate thereof.
 2. A semicarbazide as claimed in claim 1, which is offormula II

wherein R¹, R³, A and k have the meaning indicated in claim 1 and W isS(O)_(k)A, S(O)_(k)NHA, CF₃, COOA, CH₂NHA, CN or OA, and i is 0, 1 or 2.3. A compound which is:4′-[3-(3-amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(1),4′-[3-(3-(N²-hydroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(2),4′-[3-(3-amidinophenyl)-2-methylcarbazoylamino]biphenyl-2-sulfonamide(3),1-(3-amidinophenyl)-2-methyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(4),4′-[3-(3-amidinophenyl)-2-ethylcarbazoylamino]biphenyl-2-sulfonamide(5),1-(3-amidinophenyl)-2-ethyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(6),4′-[3-(3-amidinophenyl)-2-isopropylcarbazoylamino]biphenyl-2-sulfonamide(7),1-(3-amidinophenyl)-2-isopropyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(8),4′-[3-(3-amidinophenyl)-2-butylcarbazoylamino]biphenyl-2-sulfonamide(9),1-(3-amidinophenyl)-2-butyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(10),4′-[3-(3-amidinophenyl)-2-isobutylcarbazoylamino]biphenyl-2-sulfonamide(11),1-(3-amidinophenyl)-2-isobutyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(12),4′-[3-(3-amidinophenyl)-2-pentylcarbazoylamino]biphenyl-2-sulfonamide(13),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-pentylsemicarbazide(14),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide(15),4′-[3-(3-amidinophenyl)-2-(2-butyl)carbazoylamino]biphenyl-2-sulfonamide(16),1-(3-amidinophenyl)-2-(2-butyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(17),4′-[3-(3-amidinophenyl)-2-(cyclohexylmethyl)carbazoylamino]biphenyl-2-sulfonamide(18),1-(3-amidinophenyl)-2-(cyclohexylmethyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(19),4′-[3-(3-amidinophenyl)-2-benzylcarbazoylamino]biphenyl-2-sulfonamide(20),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(21),1-(3-N-²-hydroxyamidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(22),4′-[3-(3-amidinophenyl)-2-phenylcarbazoylamino]biphenyl-2-sulfonamide(23),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylsemicarbazide(24), methylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl-(iminomethyl)]carbamate(25), 2,2,2-trichloroethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazido]phenyl(iminomethyl)]carbamate(26), S-ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]thiocarbamate(27), 4-methoxybenzylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(28), ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(29), propylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(30), butylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(31), isopropylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(32), isobutylN-[3-[2-benzyl4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(33), allylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(34), phenylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(35), 2-fluorophenylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(36),2-benzyl-1-[3-(N¹-(methylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(37),2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-1-[3-(N¹-(phenylcarboxy)¹midino)phenyl]semicarbazide(38),2-benzyl-1-[3-(N¹-(isobutylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(39),2-benzyl-1-[3-[N¹-(2-methylcarboxy-2-propoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(40),2-benzyl-1-[3-[N¹-(1-(methylcarboxy)ethoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(41), 1-methyl-4-piperidinylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(42), 2-(4-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(43), 5-methyl-2-oxo-1,3-dioxol-4-ylmethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(44), 2-(3-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(45), 2-(N,N-diethylamino)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(46), 2-(N-morpholinyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(47),1-(3-amidinophenyl)-2-(2-fluorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(48),1-(3-amidinophenyl)-2-(2-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(49),1-(3-amidinophenyl)-2-(2-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(50),1-(3-amidinophenyl)-2-(3-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(51),4-[1-(3-amidinophenylamino)-3-(2′-methylsulfonylbiphenyl-4-yl)ureidomethyl]-benzoicacid (52),1-(3-amidinophenyl)-2-(3-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(53),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethyl-benzyl)semicarbazide (54),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethyl-benzyl)semicarbazide (55),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethoxybenzyl)semicarbazide (56),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(57),1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(58),1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(59),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(60),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(61),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(62),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(63),1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(64),1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(65), ethyl2-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-acetate(66), ethyl3-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-propionate(67),4′-[3-(3-amidinophenyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]carbazoylamino]-biphenyl-2-sulfonamide(68),4′-[3-(3-amidinophenyl)-2-(2-methoxyethyl)carbazoylamino]biphenyl-2-sulfonamide(69),4′-[3-(3-amidinophenyl)-2-(methoxymethyl)carbazoylamino]biphenyl-2-sulfonamide(70),4′-[3-(3-amidinophenyl)-2-(4-methoxybutyl)carbazoylamino]biphenyl-2-sulfonamide(71),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(72),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoro-methylbenzyl)semicarbazide (73),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoro-methylbenzyl)semicarbazide (74),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoro-methylbenzyl)semicarbazide (75),1-(3-aminomethylphenyl)-2-benzyl-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)semicarbazide(76),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide(77),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(78),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(79),1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(80),1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(81),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(82),1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(83),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(84),1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(85),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide (86),1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfony-3,5-difluoro-biphenyl-4-yl)-semicarbazide(87),1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(88),2-Benzyl-1-[3-(N¹-methoxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide (89),2-Benzyl-1-[3-(N1-ethoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide (90),2-Benzyl-1-[3-(N1-vinyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide (91),2-Benzyl-1-[3-(N1-benzyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide (92),2-Benzyl-1-[3-(N1-isopropoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide (93),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(94),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(95),1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide (96),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl4-yl)-semicarbazide(97),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(98),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(99),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(100),1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3,5-difluorobiphenyl-4-yl)-semicarbazide(101),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(102),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(103), or1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(104).
 4. A compound of formula III:

wherein P and P′ are identical or different and are each a protectivegroup for nitrogen, R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R⁵ is —CHal₃, —O(C═O)A or

A is H, or an unbranched, branched or cyclic alkyl having 1-20 C atoms,Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, and mis 0 or
 1. 5. A compound of formula IV

wherein R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms, in whichone or two CH₂ groups are optionally each independently of one anotherreplaced by an O or S atom, or is Ar, Ar′, X or Hal, P and P′ areidentical or different and are each a protective group for nitrogen, R⁵is —CHal₃, —O(C═O)A or

A is H, or an unbranched, branched or cyclic alkyl having 1-20 C atoms,Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 0or 1, X is —(CH₂)_(n)—Y, and Y is —COOA, or


6. A compound of formula V

wherein R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms, in whichone or two CH₂ groups are optionally each independently of one anotherreplaced by an O or S atom, or is Ar, Ar′, X or Hal, P is a protectivegroup for nitrogen, R⁵ is —CHal₃, —O(C═O)A or

A is H, or an unbranched, branched or cyclic alkyl having 1-20 C atoms,Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 0or 1, X is —(CH₂)_(n)—Y, and Y is —COOA, or


7. A compound of formula VI

wherein R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms, in whichone or two CH₂ groups are optionally each independently of one anotherreplaced by an O or S atom, or is Ar, Ar′, X or Hal, P is a protectivegroup for nitrogen, i is 0, 1, 2, 3 or 4, l is iodine, R⁵ is —CHal₃,—O(C═O)A or

A is H, or an unbranched, branched or cyclic alkyl having 1-20 C atoms,Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 0or 1, X is —(CH₂)_(n)—Y, and Y is —COOA, or


8. A compound of formula VII

wherein R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms, in whichone or two CH₂ groups are optionally each independently of one anotherreplaced by an O or S atom, or is Ar, Ar′, X or Hal, P is a protectivegroup for nitrogen, i is 0, 1, 2, 3 or 4, R⁴ is phenyl monosubstitutedby S(O)_(k)A, S(O)_(k)NHA, CF₃, COOA, CH₂NHA, CH₂NHA, CN or OA, k is 0,1 or 2, R⁵ is —CHal₃, —O(C═O)A or

A is H, or an unbranched, branched or cyclic alkyl having 1-20 C atoms,Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 0or 1, X is —(CH₂)_(n)—Y, and Y is —COOA, or


9. A process for preparing a compound of formula I, comprising at leastone of the reaction steps a, b, c, or d, a) converting a compoundformula III to a compounds of formula IV,

wherein P and P′ are identical or different and are each a protectivegroup for nitrogen, R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or—C(═NH)—NH₂, which is optionally monosubstituted by —OH, —OCOOA,—OCOO(CH₂)_(n)N(A)₂, —OCOO(CH₂)_(m)—Het, —CO—C(A)₂—R⁵, —COOA, —COSA,—COOAr, —COOAr′,

R⁵ is —CHal₃, —O(C═O)A or

A is H, or an unbranched, branched or cyclic alkyl having 1-20 C atoms,Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA, orS(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which is optionally unsubstituted orsubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, and mis 0 or 1,

wherein R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms,in which one or two CH₂ groups are optionally each independently of oneanother replaced by an O or S atom, or is Ar, Ar′, X or Hal, X is—(CH₂)_(n)—Y, Y is COOA, or

and wherein R¹, P, P′, Ar, Ar′ and Hal are as defined for formula III,b) converting a compounds of the formula IV to give a compounds offormula V,

wherein in both the compounds of formula IV and V, the groups R₁, P, P′,and R³ are as defined in a) c) converting a compound of formula V to acompound of formula VI,

wherein in both the compounds of formula V and VI, the groups R₁, R₃ andP are as defined in a), i is 0, 1, 2, 3 or 4, and i is iodine, or d)converting a compound of formula VI to a compound of the formula VII

wherein in both the compounds of formula VI and VII, the groups R¹, R³,P, I, and i are as defined in c), and R⁴ is phenyl monosubstituted byS(O)_(k)A, S(O)_(k)NHA, CF₃, COOA, CH²NHA, CN or OA, wherein k is 0, 1or 2, and A is as defined in a).
 10. A pharmaceutical compositioncomprising a compound of formula I according to claim 1 and/or apharmaceutically acceptable salt or solvate thereof and apharmaceutically acceptable carrier.
 11. A method of treatingthromboses, myocardial infarct, arteriosclerosis, inflammation,apoplexy, angina pectoris, restenosis after angioplasty, intermittentclaudication tumor, and/or tumor metastases comprising administering toa patient in need thereof an effective amount of a pharmaceuticalcomposition according to claim
 10. 12. A semicarbazide as claimed inclaim 1, which is of the formula

wherein R¹ is —C(═NH)—NH₂, or —C(═NH)—NH—OH, R³ is an unbranched orbranched alkyl having 1-5 C atoms, and z is —NH₂, or —CH₃.
 13. Asemicarbazide as claimed in claim 1, which is of the formula

wherein R₁ is —C(═NH)—NH₂, or —C(═NH)—NH—OH, z is —NH₂, or —CH₃, and R₃is a branched or cyclic alkyl having 1-7 carbon atoms or Ar or Ar′, Aris phenyl, and Ar′ is —CH₂—Ar.
 14. A semicarbazide, which is of theformula

wherein R¹ is —C(═NH)═NH₂, which is monosubstituted by —COO—C(A)₂—R⁵,—COOA, —COSA, —COOAr, or —COOAr′, Ar is phenyl, which is unsubstitutedor mono-substituted by A, OA, or F, Ar′ is —CH₂—Ar, A is H or anunbranched, or branched alkyl or alkenyl having 1-4 C atoms, R⁵ is—CHal₃, and Hal is Cl.
 15. A semicarbazide, which is of the formula

wherein B and C are each independently H or F, and R³ is

wherein Q is absent or is CH₃, F, Cl, COOH, CF₃, or OCF₃.
 16. A compoundwhich is:4′-[3-(3-amidinophenyl)-2-(cyclohexylmethyl)carbazoylamino]biphenyl-2-sulfonamide(18),1-(3-amidinophenyl)-2-(cyclohexylmethyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(19), 2,2,2-trichloroethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(26), allylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(34),2-benzyl-1-[3-(N¹-(methylcarboxy)amidino)phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(37),2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-1-[3-(N¹-(phenylcarboxy)amidino)phenyl]semicarbazide(38),2-benzyl-1-[3-(N¹-(isobutylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(39), 1-methyl-4-piperidinylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(42), 2-(4-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(43), 5-methyl-2-oxo-1,3-dioxol-4-ylmethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(44), 2-(3-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(45), 2-(N,N-diethylamino)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(46), 2-(N-morpholinyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(47),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethoxy-benzyl)semicarbazide (56),4′-[3-(3-amidinophenyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]carbazoylamino]biphenyl-2-sulfonamide(68),2-Benzyl-1-[3-(N1-ethoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(90),2-Benzyl-1-[3-(N1-vinyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(91),2-Benzyl-1-[3-(N1-benzyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(92),2-Benzyl-1-[3-(N1-isopropoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(93).
 17. A compound according to claim 1, which is:4′-[3-(3-amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(1),4′-[3-(3-(N²-hydroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(2),4′-[3-(3-amidinophenyl)-2-methylcarbazoylamino]biphenyl-2-sulfonamide(3),1-(3-amidinophenyl)-2-methyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(4),4′-[3-(3-amidinophenyl)-2-ethylcarbazoylamino]biphenyl-2-sulfonamide(5),1-(3-amidinophenyl)-2-ethyl4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide(6),4′-[3-(3-amidinophenyl)-2-isopropylcarbazoylamino]biphenyl-2-sulfonamide(7),1-(3-amidinophenyl)-2-isopropyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(8),4′-[3-(3-amidinophenyl)-2-butylcarbazoylamino]biphenyl-2-sulfonamide(9),1-(3-amidinophenyl)-2-butyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(10),4′-[3-(3-amidinophenyl)-2-isobutylcarbazoylamino]biphenyl-2-sulfonamide(11),1-(3-amidinophenyl)-2-isobutyl4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(12),4′-[3-(3-amidinophenyl)-2-pentylcarbazoylamino]biphenyl-2-sulfonamide(13),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-pentylsemicarbazide(14),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide(15),4′-[3-(3-amidinophenyl)-2-(2-butyl)carbazoylamino]biphenyl-2-sulfonamide(16),1-(3-amidinophenyl)-2-(2-butyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(17),4′-[3-(3-amidinophenyl)-2-benzylcarbazoylamino]biphenyl-2-sulfonamide(20),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(21),1-(3-N-²-hydroxyamidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(22),4′-[3-(3-amidinophenyl)-2-phenylcarbazoylamino]biphenyl-2-sulfonamide(23),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylsemicarbazide(24), methylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(25), S-ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]thiocarbamate(27), 4-methoxybenzylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(28), ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(29), propylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(30), butylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(31), isopropylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(32), isobutylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(33), phenylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(35), 2-fluorophenylN-[3-[2-benzyl4-(2′-methylsulfonylbiphenyl4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(36),2-benzyl-1-[3-[N¹-(2-methylcarboxy-2-propoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(40),2-benzyl-1-[3-[N¹-(1-(methylcarboxy)ethoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(41),1-(3-amidinophenyl)-2-(2-fluorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(48),1-(3-amidinophenyl)-2-(2-methylbenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide(49),1-(3-amidinophenyl)-2-(2-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide(50),1-(3-amidinophenyl)-2-(3-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(51),4-[1-(3-amidinophenylamino)-3-(2′-methylsulfonylbiphenyl-4-yl)ureidomethyl]-benzoicacid (52),1-(3-amidinophenyl)-2-(3-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(53),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethyl-benzyl)semicarbazide (54),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethyl-benzyl)semicarbazide (55),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(57),1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(58),1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(59),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(60),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(61),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(62),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(63),1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(64),1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(65), ethyl2-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-acetate(66), ethyl3-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-propionate(67),4′-[3-(3-amidinophenyl)-2-(2-methoxyethyl)carbazoylamino]biphenyl-2-sulfonamide(69),4′-[3-(3-amidinophenyl)-2-(methoxymethyl)carbazoylamino]biphenyl-2-sulfonamide(70),4′-[3-(3-amidinophenyl)-2-(4-methoxybutyl)carbazoylamino]biphenyl-2-sulfonamide(71),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(72),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoro-methylbenzyl)semicarbazie (73),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoro-methylbenzyl)semicarbazie (74),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoro-methylbenzyl)semicarbazie (75),1-(3-aminomethylphenyl)-2-benzyl-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)semicarbazide(76),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide(77),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(78),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(79),1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(80),1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(81),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(82),1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(83),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(84),1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(85),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(86),1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(87),1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(88),2-Benzyl-1-[3-(N¹-methoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(89),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(94),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(95),1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(96),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(97),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(98),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(99),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(100),1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3,5-difluorobiphenyl-4-yl)-semicarbazide(101),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(102),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(103), or1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(104).